{"gene":"RTN1","run_date":"2026-04-28T20:42:06","timeline":{"discoveries":[{"year":1994,"finding":"RTN1 protein isoforms (NSP-A and NSP-C) are anchored to membranes of the endoplasmic reticulum via their common hydrophobic carboxy-terminal domain; deletion mutant analysis revealed that this C-terminal hydrophobic portion is critical for membrane binding. NSP-A co-localizes with SERCA2b, a Ca2+-ATPase of the ER.","method":"In vitro translation, immunoprecipitation, Western blot, immunocytochemistry, deletion mutant analysis, subcellular fractionation","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 — deletion mutagenesis + fractionation + co-localization, foundational study replicated by subsequent work","pmids":["7844160"],"is_preprint":false},{"year":1994,"finding":"NSP-A and NSP-B form supramolecular aggregates (>500 kDa) associated with the membranous fraction of cells, solubilizable by Triton X-100; NSP-B exists in phosphorylated (45 kDa) and non-phosphorylated forms.","method":"Gel filtration, immunoprecipitation, immunoblotting, 2D-PAGE, transfection of COS-1 cells","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical methods in single study","pmids":["7720728"],"is_preprint":false},{"year":1996,"finding":"NSP-C (RTN1-C) localizes to the endoplasmic reticulum and is retained in the membranous fraction solubilizable by Triton X-100; under native immunoprecipitation conditions, NSP-C does not need to associate with NSP-A to form high molecular weight RTN complexes.","method":"Immunofluorescence of transfected COS-1 cells, cell fractionation, immunoprecipitation under native conditions, immunoblotting","journal":"European journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (fractionation, IP, IF) in single study","pmids":["8900485"],"is_preprint":false},{"year":1996,"finding":"The human NSP/RTN1 gene uses multiple promoters rather than alternative splicing of internal exons to generate distinct mRNA isoforms encoding RTN1 protein isoforms with unique N-terminal regions but a common C-terminal domain.","method":"Genomic clone analysis, comparison of genomic and cDNA sequences, lambda phage and YAC library screening","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — genomic structural analysis with sequencing evidence","pmids":["8833145"],"is_preprint":false},{"year":1996,"finding":"RTN1 (s-rex/NSP) mRNAs are compartmentalized within neurons: in certain adult brain neurons, most of the shorter s-rexs mRNA and a substantial amount of s-rexb mRNA localize to the axonal pole of the cell body, targeting the encoded proteins to specific neuronal regions.","method":"Subtractive hybridization, in situ hybridization, immunolocalization","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — localization tied to functional compartmentalization in neurons","pmids":["8793864"],"is_preprint":false},{"year":2007,"finding":"ER localization of RTN1-A requires its two long hydrophobic segments in the C-terminal domain; each segment alone is sufficient for ER targeting, but loss of both results in cytosolic localization. The length of the hydrophobic segment also determines ER retention vs. Golgi localization.","method":"EGFP fusion constructs, deletion mutagenesis, fluorescence microscopy in transfected cells","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis with defined functional readout (ER vs. Golgi vs. cytosol localization)","pmids":["17303085"],"is_preprint":false},{"year":2009,"finding":"The C-terminal region of RTN1-C (residues 186-208) contains a consensus sequence homologous to H4 histone and binds and condenses nucleic acids. This region also interacts with HDAC8, and its binding can be regulated by acetylation-deacetylation, suggesting RTN1-C function may be regulated by this mechanism.","method":"Electrophoretic mobility shift, fluorescence spectroscopy, kinetic assays with acetylated peptide, sequence homology analysis","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple in vitro biochemical assays in single study","pmids":["19140693"],"is_preprint":false},{"year":2010,"finding":"The RTN1-C C-terminal peptide (residues 186-208) binds copper and nickel ions via an ATCUN-binding motif, and the resulting metal-peptide complex has nuclease activity and inhibits histone deacetylase (HDAC) activity at micromolar concentrations.","method":"UV-vis spectroscopy, CD, NMR, kinetic HDAC assays, DNA cleavage assays","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 — multiple orthogonal in vitro methods, single lab","pmids":["20000484"],"is_preprint":false},{"year":2012,"finding":"The RTN1-C C-terminal region contains a metal ion binding motif (HxE/D) that binds copper and nickel; metal binding may contribute to the formation of RTN multiprotein complexes.","method":"UV-vis, CD, multidimensional NMR, biological HDAC assays","journal":"Metallomics","confidence":"Medium","confidence_rationale":"Tier 1-2 — multiple spectroscopic methods, single lab","pmids":["22522967"],"is_preprint":false},{"year":2014,"finding":"RTN1-C physically interacts with MANF (mesencephalic astrocyte-derived neurotrophic factor) in the ER; RTN1-C knockdown reduces MANF localization to the ER, indicating RTN1-C regulates MANF ER retention.","method":"Yeast two-hybrid screen of human fetal brain cDNA library, GST pull-down, co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown","journal":"Acta biochimica et biophysica Sinica","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding assays (Y2H, GST pull-down, Co-IP) plus localization with functional consequence","pmids":["25543119"],"is_preprint":false},{"year":2015,"finding":"RTN1A interacts with PERK (an ER stress kinase) through both its N-terminal and C-terminal domains; mutation of these domains prevents RTN1A-mediated induction of ER stress. RTN1 overexpression induces ER stress and apoptosis, while knockdown attenuates ER stress and renal fibrosis in vivo.","method":"Co-immunoprecipitation, domain deletion mutagenesis, in vivo mouse knockdown (UUO and diabetic models), tunicamycin/hyperglycemia-induced ER stress assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — co-IP with domain mutagenesis + in vivo validation, replicated in multiple disease models","pmids":["26227493"],"is_preprint":false},{"year":2017,"finding":"RTN1-C mediates ischemia/reperfusion-induced apoptosis via ER stress and mitochondria-associated pathways; mechanistically, RTN1-C interacts with Bcl-xL and increases Bcl-xL localization to the ER, thereby reducing Bcl-xL anti-apoptotic activity.","method":"Co-immunoprecipitation, subcellular fractionation, rat MCAO model, OGD/R model, overexpression and siRNA knockdown, flow cytometry, Western blot","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — Co-IP demonstrating RTN1-C/Bcl-xL interaction, fractionation showing ER relocalization, in vivo confirmation","pmids":["28981095"],"is_preprint":false},{"year":2017,"finding":"RTN1 and RTN3 differentially regulate BACE1: RTN3 deficiency causes elevation of BACE1 protein levels, while RTN1 deficiency shows no direct effect on BACE1 due to compensation by upregulated RTN3. RTN1 and RTN3 expression is tightly cross-regulated in mouse brain.","method":"RTN1-null and RTN3-null mouse generation, BACE1 activity assays, immunohistochemistry, Western blot","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout models with defined molecular and cellular readouts, epistasis analysis","pmids":["28733667"],"is_preprint":false},{"year":2018,"finding":"RTN1-C knockdown in SN4741 cells inhibits surface expression of metabotropic glutamate receptor 5 (mGluR5) and attenuates intracellular Ca2+ release induced by MPP+; protective effects of RTN1-C knockdown are partially reversed by mGluR5 activation, indicating RTN1-C regulates mGluR5-mediated Ca2+ homeostasis.","method":"siRNA knockdown, Western blot for surface mGluR5, Ca2+ imaging, pharmacological receptor activation","journal":"Brain research bulletin","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway placement via pharmacological epistasis and Ca2+ imaging","pmids":["30521940"],"is_preprint":false},{"year":2018,"finding":"RTN1-C knockdown in cortical neurons reduces traumatic neuronal injury by attenuating intracellular Ca2+ overload; specifically, RTN1-C knockdown inhibits mGluR1-mediated ER Ca2+ release and suppresses STIM1 expression, thereby reducing store-operated Ca2+ entry (SOCE).","method":"siRNA knockdown, Ca2+ imaging, thapsigargin-induced SOCE assay, Western blot for STIM1, cytotoxicity and apoptosis assays","journal":"Neurochemistry international","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays linking RTN1-C to STIM1/SOCE pathway","pmids":["30352262"],"is_preprint":false},{"year":2019,"finding":"RTN1-C expression is upregulated in high glucose/OGD/R-treated neurons and exacerbates ER stress; RTN1-C knockdown reverses high glucose-aggravated cell death and relieves ER stress markers (GRP78, cleaved caspase-12, CHOP, cleaved caspase-3).","method":"shRNA knockdown, OGD/R model, Western blot, CCK-8 assay, flow cytometry, 4-PBA ER stress inhibitor","journal":"Brain research bulletin","confidence":"Medium","confidence_rationale":"Tier 2 — KD with multiple molecular readouts, chemical epistasis with ER stress inhibitor","pmids":["31002913"],"is_preprint":false},{"year":2019,"finding":"NSP-C (RTN1-C) interacts with CLOCK in mammalian cells and acts as a positive regulator of CLOCK/BMAL1-mediated E-box transcription; NSP-C knockdown suppresses E-box-mediated transcription, and this is rescued by siRNA-resistant NSP-C.","method":"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, siRNA knockdown, rescue experiment, E-box reporter assay","journal":"Cytotechnology","confidence":"Medium","confidence_rationale":"Tier 2 — Y2H + Co-IP + functional transcription assay + rescue in single study","pmids":["30600463"],"is_preprint":false},{"year":2021,"finding":"RTN1-C modulates autophagy during cerebral ischemia/reperfusion injury: RTN1-C knockdown suppresses overactivated autophagy (decreased Beclin-1 and other autophagy markers) both in vivo and in vitro, reducing brain infarct volume and neurological deficits; rapamycin (autophagy activator) treatment aggravates injury, and RTN1-C knockdown partially rescues this.","method":"Lentiviral shRNA in vivo and in vitro, rat MCAO model, OGD/R model, Western blot for autophagy markers, rapamycin pharmacological epistasis, infarct volume measurement","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo + in vitro KD with pharmacological epistasis","pmids":["33372676"],"is_preprint":false},{"year":2021,"finding":"TUG1 lncRNA down-regulates RTN1 expression by inhibiting binding of transcription factor PU.1 to the RTN1 promoter; PU.1 directly transactivates RTN1, and its inhibition by TUG1 reduces ER stress and apoptosis in diabetic nephropathy.","method":"Dual-luciferase activity assay, RNA pull-down, RIP, ChIP, adenoviral overexpression in vivo, siRNA knockdown","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP + luciferase + RIP + in vivo validation provide mechanistic placement of PU.1 as RTN1 transcriptional regulator","pmids":["34062006"],"is_preprint":false}],"current_model":"RTN1 encodes a family of ER-resident membrane proteins (RTN1-A, -B, -C) anchored via two long hydrophobic C-terminal segments; the RTN1-C isoform interacts with PERK (through N- and C-terminal domains), Bcl-xL (promoting its ER localization and reducing its anti-apoptotic activity), MANF (regulating MANF ER retention), and CLOCK (enhancing circadian transcription), and it modulates intracellular Ca2+ homeostasis through mGluR1/mGluR5 and STIM1-dependent SOCE, collectively driving ER stress, autophagy, and apoptosis in neurons and renal cells under pathological conditions; RTN1 expression is transcriptionally controlled by PU.1, which is in turn suppressed by lncRNA TUG1."},"narrative":{"teleology":[{"year":1994,"claim":"Establishing that RTN1 isoforms are ER-anchored membrane proteins resolved the fundamental question of where these neuronally enriched proteins reside and act, revealing their C-terminal hydrophobic domain as the membrane-targeting determinant.","evidence":"Deletion mutagenesis, subcellular fractionation, and immunocytochemistry in transfected cells showing co-localization with ER marker SERCA2b","pmids":["7844160","7720728"],"confidence":"High","gaps":["Precise membrane topology (hairpin vs. transmembrane) was not resolved","No functional consequence of ER localization was demonstrated"]},{"year":1996,"claim":"Demonstrating that RTN1-C independently forms high-molecular-weight ER complexes without requiring RTN1-A, and that distinct promoters generate isoforms with unique N-termini, established isoform-specific organizational principles.","evidence":"Native immunoprecipitation, cell fractionation, immunofluorescence in COS-1 cells; genomic clone and cDNA sequence comparison","pmids":["8900485","8833145","8793864"],"confidence":"High","gaps":["Functional differences between isoform-specific complexes were unknown","Identity of other complex subunits was not determined"]},{"year":2007,"claim":"Defining that each of the two C-terminal hydrophobic segments is independently sufficient for ER targeting, and that segment length controls ER versus Golgi retention, resolved the structural basis of RTN1 ER residency.","evidence":"EGFP-fusion deletion constructs with fluorescence microscopy readout in transfected cells","pmids":["17303085"],"confidence":"High","gaps":["No reconstitution of membrane curvature or tubulation activity","In vivo relevance of hydrophobic segment length variants was not tested"]},{"year":2009,"claim":"Identifying a histone H4-homologous region in RTN1-C that binds and condenses nucleic acids and interacts with HDAC8, regulated by acetylation, revealed an unexpected potential for chromatin-related regulation by an ER protein.","evidence":"EMSA, fluorescence spectroscopy, kinetic assays with acetylated peptide, sequence homology analysis","pmids":["19140693","20000484","22522967"],"confidence":"Medium","gaps":["In vivo relevance of nucleic acid binding by an ER-resident protein is unclear","Metal-binding nuclease activity demonstrated only in vitro with isolated peptides","Not independently confirmed by another laboratory"]},{"year":2014,"claim":"Showing that RTN1-C physically interacts with MANF and is required for MANF ER retention provided the first evidence that RTN1 functions as an ER retention factor for a secreted neurotrophic factor.","evidence":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown in cells","pmids":["25543119"],"confidence":"High","gaps":["Mechanism of retention (direct anchoring vs. retrieval) was not distinguished","In vivo consequences of MANF mislocalization upon RTN1 loss were not tested"]},{"year":2015,"claim":"Demonstrating that RTN1A directly interacts with the ER stress kinase PERK through both N- and C-terminal domains, and that RTN1 overexpression induces ER stress while knockdown attenuates renal fibrosis in vivo, established RTN1 as an upstream activator of the UPR.","evidence":"Co-immunoprecipitation with domain deletion mutagenesis, in vivo mouse UUO and diabetic models with RTN1 knockdown","pmids":["26227493"],"confidence":"High","gaps":["Whether RTN1 activates PERK by direct conformational change or by altering ER membrane structure was not resolved","Specificity for PERK versus other UPR sensors (IRE1, ATF6) was not fully addressed"]},{"year":2017,"claim":"Identifying RTN1-C as a binding partner of Bcl-xL that redirects Bcl-xL to the ER and reduces its anti-apoptotic activity linked RTN1-C to mitochondria-associated apoptotic pathways during ischemia/reperfusion injury.","evidence":"Co-immunoprecipitation, subcellular fractionation, rat MCAO model, OGD/R model, siRNA knockdown","pmids":["28981095"],"confidence":"High","gaps":["Whether Bcl-xL sequestration is the primary pro-apoptotic mechanism or secondary to ER stress was not resolved","Binding interface on Bcl-xL was not mapped"]},{"year":2018,"claim":"Showing that RTN1-C knockdown inhibits mGluR1/mGluR5 surface expression and STIM1-dependent store-operated Ca²⁺ entry revealed RTN1-C as a regulator of ER-to-plasma-membrane Ca²⁺ signaling in neurons.","evidence":"siRNA knockdown, Ca²⁺ imaging, thapsigargin-induced SOCE assay, pharmacological mGluR activation in neuronal cell lines and cortical neurons","pmids":["30521940","30352262"],"confidence":"Medium","gaps":["Direct physical interaction between RTN1-C and mGluR or STIM1 was not demonstrated","Whether Ca²⁺ dysregulation is upstream or downstream of ER stress was not established"]},{"year":2019,"claim":"Demonstrating that RTN1-C interacts with CLOCK and enhances CLOCK/BMAL1-mediated E-box transcription expanded RTN1-C function beyond ER stress to circadian gene regulation.","evidence":"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown with rescue, E-box luciferase reporter assay in mammalian cells","pmids":["30600463"],"confidence":"Medium","gaps":["The subcellular compartment where RTN1-C–CLOCK interaction occurs was not defined","Physiological circadian phenotype upon RTN1 loss was not tested in vivo"]},{"year":2021,"claim":"Establishing that RTN1-C drives overactivated autophagy during cerebral ischemia/reperfusion, and that its transcription is controlled by PU.1 (itself inhibited by lncRNA TUG1), placed RTN1 at the convergence of transcriptional regulation, ER stress, and autophagy.","evidence":"Lentiviral shRNA in rat MCAO and OGD/R models with rapamycin epistasis; ChIP, luciferase, RIP, and RNA pull-down for PU.1/TUG1 axis in diabetic nephropathy models","pmids":["33372676","34062006"],"confidence":"High","gaps":["Whether autophagy modulation is a direct RTN1-C function or secondary to ER stress/Ca²⁺ dysregulation is unknown","Integration of PU.1-mediated transcription with neuronal injury contexts was not tested"]},{"year":null,"claim":"Key unresolved questions include the structural basis of RTN1 membrane topology and curvature induction, whether RTN1 isoforms have non-redundant functions in vivo, and how RTN1-C coordinates its diverse interactions (PERK, Bcl-xL, CLOCK, MANF, mGluRs) in a single cell.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of RTN1 in membranes","No conditional knockout addressing isoform-specific functions","Hierarchy among RTN1-C's pro-apoptotic, Ca²⁺-regulatory, circadian, and autophagic roles is not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,11,13,14,16]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,5,9,10,11]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[10,11,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[11,15,17]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,14]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[16]}],"complexes":[],"partners":["PERK","BCL2L1","MANF","CLOCK","STIM1","HDAC8","PU.1"],"other_free_text":[]},"mechanistic_narrative":"RTN1 encodes a family of ER-resident membrane proteins (isoforms RTN1-A, -B, -C) that function as modulators of ER stress, calcium homeostasis, autophagy, and apoptosis, particularly in neurons and renal cells. All isoforms are anchored to ER membranes via two long C-terminal hydrophobic segments, each independently sufficient for ER targeting, and can form high-molecular-weight complexes [PMID:7844160, PMID:17303085, PMID:7720728]. RTN1-C interacts with PERK to induce ER stress signaling [PMID:26227493], sequesters Bcl-xL to the ER to diminish its anti-apoptotic function [PMID:28981095], regulates intracellular Ca²⁺ through mGluR1/mGluR5 surface expression and STIM1-dependent store-operated Ca²⁺ entry [PMID:30521940, PMID:30352262], and positively regulates CLOCK/BMAL1-mediated circadian transcription [PMID:30600463]. RTN1 transcription is directly activated by PU.1, which is suppressed by the lncRNA TUG1, linking RTN1 expression to ER stress and apoptosis in diabetic nephropathy [PMID:34062006]."},"prefetch_data":{"uniprot":{"accession":"Q16799","full_name":"Reticulon-1","aliases":["Neuroendocrine-specific protein"],"length_aa":776,"mass_kda":83.6,"function":"Inhibits amyloid precursor protein processing, probably by blocking BACE1 activity","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q16799/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RTN1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RTN4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RTN1","total_profiled":1310},"omim":[{"mim_id":"610243","title":"ZINC FINGER FYVE DOMAIN-CONTAINING PROTEIN 27; ZFYVE27","url":"https://www.omim.org/entry/610243"},{"mim_id":"610236","title":"LUNAPARK; LNPK","url":"https://www.omim.org/entry/610236"},{"mim_id":"604277","title":"SPASTIN; SPAST","url":"https://www.omim.org/entry/604277"},{"mim_id":"604252","title":"BETA-SITE AMYLOID BETA A4 PRECURSOR PROTEIN-CLEAVING ENZYME 1; BACE1","url":"https://www.omim.org/entry/604252"},{"mim_id":"604249","title":"RETICULON 3; RTN3","url":"https://www.omim.org/entry/604249"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":444.9}],"url":"https://www.proteinatlas.org/search/RTN1"},"hgnc":{"alias_symbol":[],"prev_symbol":["NSP"]},"alphafold":{"accession":"Q16799","domains":[{"cath_id":"1.20.5","chopping":"667-719","consensus_level":"medium","plddt":90.776,"start":667,"end":719}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16799","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16799-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16799-F1-predicted_aligned_error_v6.png","plddt_mean":48.09},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RTN1","jax_strain_url":"https://www.jax.org/strain/search?query=RTN1"},"sequence":{"accession":"Q16799","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16799.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16799/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16799"}},"corpus_meta":[{"pmid":"28981095","id":"PMC_28981095","title":"RTN1-C mediates cerebral ischemia/reperfusion injury via ER stress and mitochondria-associated apoptosis pathways.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28981095","citation_count":212,"is_preprint":false},{"pmid":"7844160","id":"PMC_7844160","title":"NSP-encoded reticulons, neuroendocrine proteins of a novel gene family associated with membranes of the endoplasmic reticulum.","date":"1994","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/7844160","citation_count":107,"is_preprint":false},{"pmid":"26227493","id":"PMC_26227493","title":"RTN1 mediates progression of kidney disease by inducing ER stress.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26227493","citation_count":82,"is_preprint":false},{"pmid":"638782","id":"PMC_638782","title":"Neuron specific protein (NSP) in neuroblastoma cells: relation to differentiation.","date":"1978","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/638782","citation_count":79,"is_preprint":false},{"pmid":"20624762","id":"PMC_20624762","title":"NSP-interacting kinase, NIK: a transducer of plant defence signalling.","date":"2010","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/20624762","citation_count":60,"is_preprint":false},{"pmid":"12837950","id":"PMC_12837950","title":"A novel Arabidopsis acetyltransferase interacts with the geminivirus movement protein NSP.","date":"2003","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/12837950","citation_count":56,"is_preprint":false},{"pmid":"27990154","id":"PMC_27990154","title":"NSP-Dependent Simple Nitrile Formation Dominates upon Breakdown of Major Aliphatic Glucosinolates in Roots, Seeds, and Seedlings of Arabidopsis thaliana Columbia-0.","date":"2016","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/27990154","citation_count":48,"is_preprint":false},{"pmid":"8900485","id":"PMC_8900485","title":"Neuroendocrine-specific protein C (NSP-C): subcellular localization and differential expression in relation to NSP-A.","date":"1996","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8900485","citation_count":44,"is_preprint":false},{"pmid":"8833145","id":"PMC_8833145","title":"Genomic organization of the human NSP gene, prototype of a novel gene family encoding reticulons.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8833145","citation_count":38,"is_preprint":false},{"pmid":"19140693","id":"PMC_19140693","title":"Nucleic acid binding of the RTN1-C C-terminal region: toward the functional role of a reticulon protein.","date":"2009","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19140693","citation_count":38,"is_preprint":false},{"pmid":"28733667","id":"PMC_28733667","title":"RTN1 and RTN3 protein are differentially associated with senile plaques in Alzheimer's brains.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28733667","citation_count":36,"is_preprint":false},{"pmid":"7518032","id":"PMC_7518032","title":"Molecular analysis of expression in rat brain of NSP-A, a novel neuroendocrine-specific protein of the endoplasmic reticulum.","date":"1994","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/7518032","citation_count":35,"is_preprint":false},{"pmid":"9560466","id":"PMC_9560466","title":"Neuronal differentiation is accompanied by NSP-C expression.","date":"1998","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/9560466","citation_count":35,"is_preprint":false},{"pmid":"30405819","id":"PMC_30405819","title":"Anticancer effects of curcumin on nude mice bearing lung cancer A549 cell subsets SP and NSP cells.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30405819","citation_count":34,"is_preprint":false},{"pmid":"8062278","id":"PMC_8062278","title":"NSP-encoded reticulons are neuroendocrine markers of a novel category in human lung cancer diagnosis.","date":"1994","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/8062278","citation_count":32,"is_preprint":false},{"pmid":"22081014","id":"PMC_22081014","title":"NSP-Cas protein structures reveal a promiscuous interaction module in cell signaling.","date":"2011","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22081014","citation_count":31,"is_preprint":false},{"pmid":"16461385","id":"PMC_16461385","title":"The geminivirus nuclear shuttle protein NSP inhibits the activity of AtNSI, a vascular-expressed Arabidopsis acetyltransferase regulated with the sink-to-source transition.","date":"2006","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16461385","citation_count":31,"is_preprint":false},{"pmid":"17427198","id":"PMC_17427198","title":"AND-34/BCAR3 differs from other NSP homologs in induction of anti-estrogen resistance, cyclin D1 promoter activation and altered breast cancer cell morphology.","date":"2007","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17427198","citation_count":31,"is_preprint":false},{"pmid":"17499404","id":"PMC_17499404","title":"Chimeric tymovirus-like particles displaying foot-and-mouth disease virus non-structural protein epitopes and its use for detection of FMDV-NSP antibodies.","date":"2007","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/17499404","citation_count":30,"is_preprint":false},{"pmid":"7720728","id":"PMC_7720728","title":"Subcellular localization and supramolecular organization of neuroendocrine-specific protein B (NSP-B) in small cell lung cancer.","date":"1994","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7720728","citation_count":29,"is_preprint":false},{"pmid":"15452236","id":"PMC_15452236","title":"Interaction of the movement protein NSP and the Arabidopsis acetyltransferase AtNSI is necessary for Cabbage leaf curl geminivirus infection and pathogenicity.","date":"2004","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15452236","citation_count":29,"is_preprint":false},{"pmid":"8793864","id":"PMC_8793864","title":"Intracellular compartmentalization of two differentially spliced s-rex/NSP mRNAs in neurons.","date":"1996","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/8793864","citation_count":28,"is_preprint":false},{"pmid":"21946290","id":"PMC_21946290","title":"Validation of an r3AB1-FMDV-NSP ELISA to distinguish between cattle infected and vaccinated with foot-and-mouth disease virus.","date":"2011","source":"Journal of virological methods","url":"https://pubmed.ncbi.nlm.nih.gov/21946290","citation_count":26,"is_preprint":false},{"pmid":"22798490","id":"PMC_22798490","title":"Integrity and function of the Saccharomyces cerevisiae spindle pole body depends on connections between the membrane proteins Ndc1, Rtn1, and Yop1.","date":"2012","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22798490","citation_count":24,"is_preprint":false},{"pmid":"8275708","id":"PMC_8275708","title":"Regional mapping of the human NSP gene to chromosome region 14q21-->q22 by fluorescence in situ hybridization analysis.","date":"1994","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8275708","citation_count":22,"is_preprint":false},{"pmid":"7419623","id":"PMC_7419623","title":"Protein labelling with 3H-NSP (N-succinimidyl-[2,3-3H]propionate).","date":"1980","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/7419623","citation_count":21,"is_preprint":false},{"pmid":"9031629","id":"PMC_9031629","title":"Rat and chicken s-rex/NSP mRNA: nucleotide sequence of main transcripts and expression of splice variants in rat tissues.","date":"1997","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9031629","citation_count":21,"is_preprint":false},{"pmid":"33797663","id":"PMC_33797663","title":"Novel mutations in NSP-1 and PLPro of SARS-CoV-2 NIB-1 genome mount for effective therapeutics.","date":"2021","source":"Journal, genetic engineering & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/33797663","citation_count":20,"is_preprint":false},{"pmid":"12615437","id":"PMC_12615437","title":"Development of a foot-and-mouth disease NSP ELISA and its comparison with differential diagnostic methods.","date":"2003","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/12615437","citation_count":20,"is_preprint":false},{"pmid":"9272435","id":"PMC_9272435","title":"Neuroendocrine-specific protein (NSP)-reticulons as independent markers for non-small cell lung cancer with neuroendocrine differentiation. An in vitro histochemical study.","date":"1997","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9272435","citation_count":20,"is_preprint":false},{"pmid":"9227337","id":"PMC_9227337","title":"A comparison of NSP-reticulons with conventional neuroendocrine markers in immunophenotyping of lung cancers.","date":"1997","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/9227337","citation_count":20,"is_preprint":false},{"pmid":"19704847","id":"PMC_19704847","title":"NSP-interacting GTPase: A cytosolic protein as cofactor for nuclear shuttle proteins.","date":"2008","source":"Plant signaling & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/19704847","citation_count":19,"is_preprint":false},{"pmid":"14584613","id":"PMC_14584613","title":"Antigenic analysis of nonstructural protein (NSP) 4 of group A avian rotavirus strain PO-13.","date":"2003","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14584613","citation_count":19,"is_preprint":false},{"pmid":"31679961","id":"PMC_31679961","title":"A novel free radical scavenger, NSP-116, ameliorated the brain injury in both ischemic and hemorrhagic stroke models.","date":"2019","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31679961","citation_count":15,"is_preprint":false},{"pmid":"17303085","id":"PMC_17303085","title":"Two hydrophobic segments of the RTN1 family determine the ER localization and retention.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17303085","citation_count":14,"is_preprint":false},{"pmid":"20237420","id":"PMC_20237420","title":"NSP 5a3a's link to nuclear-cyto proteins B23 and hnRNP-L between normal and aberrant breast cell lines.","date":"2010","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/20237420","citation_count":14,"is_preprint":false},{"pmid":"27151507","id":"PMC_27151507","title":"Protective effects of NSP-116, a novel imidazolyl aniline derivative, against light-induced retinal damage in vitro and in vivo.","date":"2016","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27151507","citation_count":13,"is_preprint":false},{"pmid":"31300662","id":"PMC_31300662","title":"Cassava cell wall characterization and degradation by a multicomponent NSP-targeting enzyme (NSPase).","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31300662","citation_count":13,"is_preprint":false},{"pmid":"20000484","id":"PMC_20000484","title":"Reticulon RTN1-C(CT) peptide: a potential nuclease and inhibitor of histone deacetylase enzymes.","date":"2010","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20000484","citation_count":12,"is_preprint":false},{"pmid":"21311098","id":"PMC_21311098","title":"NSP 5a3a: a potential novel cancer target in head and neck carcinoma.","date":"2010","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/21311098","citation_count":12,"is_preprint":false},{"pmid":"23226576","id":"PMC_23226576","title":"NSP-CAS Protein Complexes: Emerging Signaling Modules in Cancer.","date":"2012","source":"Genes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23226576","citation_count":12,"is_preprint":false},{"pmid":"27450531","id":"PMC_27450531","title":"Significant effect of NSP-ase enzyme supplementation in sunflower meal-based diet on the growth and nutrient digestibility in broilers.","date":"2016","source":"Journal of animal physiology and animal nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/27450531","citation_count":11,"is_preprint":false},{"pmid":"34062006","id":"PMC_34062006","title":"LncRNA TUG1 ameliorates diabetic nephropathy via inhibition of PU.1/RTN1 signaling pathway.","date":"2021","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/34062006","citation_count":10,"is_preprint":false},{"pmid":"36089639","id":"PMC_36089639","title":"A new blocking ELISA for detection of foot-and-mouth disease non-structural protein (NSP) antibodies in a broad host range.","date":"2022","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/36089639","citation_count":10,"is_preprint":false},{"pmid":"19028514","id":"PMC_19028514","title":"Retention and tissue damage of PSP and NSP toxins in shrimp: Is cultured shrimp a potential vector of toxins to human population?","date":"2008","source":"Toxicon : official journal of the International Society on Toxinology","url":"https://pubmed.ncbi.nlm.nih.gov/19028514","citation_count":10,"is_preprint":false},{"pmid":"12908898","id":"PMC_12908898","title":"The rat as a model for pigs: comparative values for the digestibility of NSP and other macronutrients.","date":"2003","source":"The British journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/12908898","citation_count":10,"is_preprint":false},{"pmid":"8863013","id":"PMC_8863013","title":"Circadian patterns of total 24-h hydrogen and methane excretion in humans ingesting nonstarch polysaccharide (NSP) diets and the implications for indirect calorimetric and D2 18O methodologies.","date":"1996","source":"European journal of clinical nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/8863013","citation_count":10,"is_preprint":false},{"pmid":"18433331","id":"PMC_18433331","title":"Identification of a novel transcriptional repressor (HEPIS) that interacts with nsp-10 of SARS coronavirus.","date":"2008","source":"Viral immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18433331","citation_count":9,"is_preprint":false},{"pmid":"28350362","id":"PMC_28350362","title":"Ergot Alkaloids in Fattening Chickens (Broilers): Toxic Effects and Carry over Depending on Dietary Fat Proportion and Supplementation with Non-Starch-Polysaccharide (NSP) Hydrolyzing Enzymes.","date":"2017","source":"Toxins","url":"https://pubmed.ncbi.nlm.nih.gov/28350362","citation_count":9,"is_preprint":false},{"pmid":"2215070","id":"PMC_2215070","title":"Prevention of immunosuppression in stressed mice by neurotropin(NSP).","date":"1990","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/2215070","citation_count":9,"is_preprint":false},{"pmid":"20455463","id":"PMC_20455463","title":"[Integration of influenza A virus NSP gene into baculovirus genome and its expression in insect cells].","date":"2010","source":"Voprosy virusologii","url":"https://pubmed.ncbi.nlm.nih.gov/20455463","citation_count":9,"is_preprint":false},{"pmid":"25543119","id":"PMC_25543119","title":"Identification of MANF as a protein interacting with RTN1-C.","date":"2014","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/25543119","citation_count":8,"is_preprint":false},{"pmid":"31348897","id":"PMC_31348897","title":"Seroepidemiology of foot and mouth disease (FMD) virus non-structural protein (NSP) antibodies in the livestock of Oman.","date":"2019","source":"Acta tropica","url":"https://pubmed.ncbi.nlm.nih.gov/31348897","citation_count":8,"is_preprint":false},{"pmid":"35403083","id":"PMC_35403083","title":"Nature's therapy for COVID-19: Targeting the vital non-structural proteins (NSP) from SARS-CoV-2 with phytochemicals from Indian medicinal plants.","date":"2020","source":"Phytomedicine plus : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35403083","citation_count":8,"is_preprint":false},{"pmid":"31002913","id":"PMC_31002913","title":"RTN1-C is involved in high glucose-aggravated neuronal cell subjected to oxygen-glucose deprivation and reoxygenation injury via endoplasmic reticulum stress.","date":"2019","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/31002913","citation_count":7,"is_preprint":false},{"pmid":"33372676","id":"PMC_33372676","title":"RTN1-C mediates cerebral ischemia/reperfusion injury via modulating autophagy.","date":"2021","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/33372676","citation_count":7,"is_preprint":false},{"pmid":"35396867","id":"PMC_35396867","title":"Partial sequence conservation of SARS-CoV-2 NSP-2, NSP-12, and Spike in stool samples from Abadan, Iran.","date":"2022","source":"Biotechnology and applied biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35396867","citation_count":6,"is_preprint":false},{"pmid":"34193689","id":"PMC_34193689","title":"Free-Radical Scavenger NSP-116 Protects the Corneal Epithelium against UV-A and Blue LED Light Exposure.","date":"2021","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/34193689","citation_count":6,"is_preprint":false},{"pmid":"11851014","id":"PMC_11851014","title":"Studies on the mode of action of non-starch-polysaccharides (NSP)-degrading enzymes in vitro. 2. Communication: effects on nutrient release and hydration properties.","date":"2001","source":"Archiv fur Tierernahrung","url":"https://pubmed.ncbi.nlm.nih.gov/11851014","citation_count":6,"is_preprint":false},{"pmid":"32799169","id":"PMC_32799169","title":"Porcine reproductive and respiratory syndrome virus (PRRSV) non-structural protein (NSP)1 transcriptionally inhibits CCN1 and CCN2 expression by blocking ERK-AP-1 axis in pig macrophages in vitro.","date":"2020","source":"Research in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/32799169","citation_count":6,"is_preprint":false},{"pmid":"34607459","id":"PMC_34607459","title":"Spindle Dynamics during Meiotic Development of the Fungus Podospora anserina Requires the Endoplasmic Reticulum-Shaping Protein RTN1.","date":"2021","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/34607459","citation_count":5,"is_preprint":false},{"pmid":"22170762","id":"PMC_22170762","title":"A novel dual signaling axis for NSP 5a3a induced apoptosis in head and neck carcinoma.","date":"2011","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/22170762","citation_count":5,"is_preprint":false},{"pmid":"29087781","id":"PMC_29087781","title":"Evaluation of immunogenicity and safety of VARIVAX™ New Seed Process (NSP) in children.","date":"2017","source":"Human vaccines & immunotherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/29087781","citation_count":5,"is_preprint":false},{"pmid":"6173291","id":"PMC_6173291","title":"[Effect of neurotropin (NSP) on allergic reactions (author's transl)].","date":"1981","source":"Nihon yakurigaku zasshi. Folia pharmacologica Japonica","url":"https://pubmed.ncbi.nlm.nih.gov/6173291","citation_count":5,"is_preprint":false},{"pmid":"12354640","id":"PMC_12354640","title":"Differential display identifies neuroendocrine-specific protein-A (NSP-A) and interferon-inducible protein 10 (IP-10) as ethanol-responsive genes in the fetal rat brain.","date":"2002","source":"Brain research. Developmental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/12354640","citation_count":5,"is_preprint":false},{"pmid":"35747917","id":"PMC_35747917","title":"[The Expression of RTN1 in Lung Adenocarcinoma and 
Its Effect on Immune Microenvironment].","date":"2022","source":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35747917","citation_count":4,"is_preprint":false},{"pmid":"30521940","id":"PMC_30521940","title":"Downregulation of RTN1-C attenuates MPP+-induced neuronal injury through inhibition of mGluR5 pathway in SN4741 cells.","date":"2018","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/30521940","citation_count":4,"is_preprint":false},{"pmid":"37764993","id":"PMC_37764993","title":"Non-Structural Proteins (Nsp): A Marker for Detection of Human Coronavirus Families.","date":"2023","source":"Pathogens (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37764993","citation_count":4,"is_preprint":false},{"pmid":"34959589","id":"PMC_34959589","title":"Understanding COVID-19 Pathogenesis: A Drug-Repurposing Effort to Disrupt Nsp-1 Binding to Export Machinery Receptor Complex.","date":"2021","source":"Pathogens (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34959589","citation_count":4,"is_preprint":false},{"pmid":"6384264","id":"PMC_6384264","title":"Identification and immunolocalization by monoclonal antibody of NSP-5, a surface polypeptide of neural cells.","date":"1984","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/6384264","citation_count":4,"is_preprint":false},{"pmid":"9850797","id":"PMC_9850797","title":"Studies on the mode of action of non-starch-polysaccharides (NSP) degrading enzymes in vitro. 1. Communication: effects on the fractions of NSP.","date":"1998","source":"Archiv fur Tierernahrung","url":"https://pubmed.ncbi.nlm.nih.gov/9850797","citation_count":4,"is_preprint":false},{"pmid":"32353571","id":"PMC_32353571","title":"BmK NSP, a new sodium channel activator from Buthus martensii Karsch, promotes neurite outgrowth in primary cultured spinal cord neurons.","date":"2020","source":"Toxicon : official journal of the International Society on Toxinology","url":"https://pubmed.ncbi.nlm.nih.gov/32353571","citation_count":4,"is_preprint":false},{"pmid":"35021142","id":"PMC_35021142","title":"Molecular dynamics simulations of the flexibility and inhibition of SARS-CoV-2 NSP 13 helicase.","date":"2022","source":"Journal of molecular graphics & modelling","url":"https://pubmed.ncbi.nlm.nih.gov/35021142","citation_count":3,"is_preprint":false},{"pmid":"30352262","id":"PMC_30352262","title":"Knockdown of RTN1-C attenuates traumatic neuronal injury through regulating intracellular Ca2+ homeostasis.","date":"2018","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/30352262","citation_count":3,"is_preprint":false},{"pmid":"22522967","id":"PMC_22522967","title":"A metal-binding site in the RTN1-C protein: new perspectives on the physiological role of a neuronal protein.","date":"2012","source":"Metallomics : integrated biometal science","url":"https://pubmed.ncbi.nlm.nih.gov/22522967","citation_count":3,"is_preprint":false},{"pmid":"39397089","id":"PMC_39397089","title":"Evaluation and comparison of performances of six commercial NSP ELISA assays for foot and mouth disease virus in Thailand.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39397089","citation_count":3,"is_preprint":false},{"pmid":"31367821","id":"PMC_31367821","title":"NSP Protein Encoded in Negative NS RNA Strand of Influenza A Virus Induces Cellular Immune Response in Infected Animals.","date":"2019","source":"Doklady. Biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/31367821","citation_count":3,"is_preprint":false},{"pmid":"36463562","id":"PMC_36463562","title":"Structural Landscape of nsp Coding Genomic Regions of SARS-CoV-2-ssRNA Genome: A Structural Genomics Approach Toward Identification of Druggable Genome, Ligand-Binding Pockets, and Structure-Based Druggability.","date":"2022","source":"Molecular biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/36463562","citation_count":3,"is_preprint":false},{"pmid":"6292017","id":"PMC_6292017","title":"Isolation of the homogeneous constituents from non-diffusible sugar-peptide (NSP) fraction originating from bovine plasma--II. The influence on cell growth of BHK-21, BHK/RSV and PR-RSH cells in vitro.","date":"1982","source":"The International journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/6292017","citation_count":3,"is_preprint":false},{"pmid":"40186280","id":"PMC_40186280","title":"Systematic follow-up investigation of NSP seroreactors and in-contact cattle and buffaloes for foot-and-mouth disease virus using probang sampling.","date":"2025","source":"BMC veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/40186280","citation_count":3,"is_preprint":false},{"pmid":"38111672","id":"PMC_38111672","title":"Inhibition of SARS-CoV-2 NSP-15 by Uridine-5'-Monophosphate Analogues Using QSAR Modelling, Molecular Dynamics Simulations, and Free Energy Landscape.","date":"2023","source":"Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society","url":"https://pubmed.ncbi.nlm.nih.gov/38111672","citation_count":2,"is_preprint":false},{"pmid":"32735863","id":"PMC_32735863","title":"Nanodisc scaffold peptide (NSPr) replaces detergent by reconstituting acyl-CoA:cholesterol acyltransferase 1 into peptidiscs.","date":"2020","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/32735863","citation_count":2,"is_preprint":false},{"pmid":"37328626","id":"PMC_37328626","title":"Development of TaqMan Probe-Based One-Step RT-qPCR Assay Targeting 2B-NSP Coding Region for Diagnosis of Foot-and-Mouth Disease in India.","date":"2023","source":"Current microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/37328626","citation_count":2,"is_preprint":false},{"pmid":"32276905","id":"PMC_32276905","title":"Effect of nose sensitive pill (NSP) on serum IFN-γ and il-4 levels in allergic rhinitis using rats model.","date":"2020","source":"Pakistan journal of pharmaceutical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32276905","citation_count":2,"is_preprint":false},{"pmid":"18793465","id":"PMC_18793465","title":"Validation of an NSP-based (negative selection pattern) gene family identification strategy.","date":"2008","source":"BMC bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/18793465","citation_count":2,"is_preprint":false},{"pmid":"37466043","id":"PMC_37466043","title":"Interactions of dietary wheat cultivars and NSP-degrading enzyme on productive performance and egg quality traits.","date":"2023","source":"Veterinary medicine and science","url":"https://pubmed.ncbi.nlm.nih.gov/37466043","citation_count":2,"is_preprint":false},{"pmid":"30600463","id":"PMC_30600463","title":"NSP-C contributes to the upregulation of CLOCK/BMAL1-mediated transcription.","date":"2019","source":"Cytotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/30600463","citation_count":2,"is_preprint":false},{"pmid":"35567667","id":"PMC_35567667","title":"Characterization of the functional domains of nuclear shuttle protein (NSP) of Indian cassava mosaic virus using green fluorescent protein as reporter.","date":"2022","source":"Virus genes","url":"https://pubmed.ncbi.nlm.nih.gov/35567667","citation_count":1,"is_preprint":false},{"pmid":"35879631","id":"PMC_35879631","title":"Pathogenomic in silico approach identifies NSP-A and Fe-IIISBP as possible drug targets in Neisseria Meningitidis MC58 and development of pharmacophores as novel therapeutic candidates.","date":"2022","source":"Molecular diversity","url":"https://pubmed.ncbi.nlm.nih.gov/35879631","citation_count":1,"is_preprint":false},{"pmid":"36456773","id":"PMC_36456773","title":"Evaluation of action of steroid molecules on SARS-CoV-2 by inhibiting NSP-15, an endoribonuclease.","date":"2022","source":"Molecular diversity","url":"https://pubmed.ncbi.nlm.nih.gov/36456773","citation_count":1,"is_preprint":false},{"pmid":"39347210","id":"PMC_39347210","title":"Computational Investigations to Identify Potent Natural Flavonoid Inhibitors of the Nonstructural Protein (NSP) 16/10 Complex Against Coronavirus.","date":"2024","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/39347210","citation_count":1,"is_preprint":false},{"pmid":"40702697","id":"PMC_40702697","title":"Discovery of a Novel MNK Inhibitor (NSP-1047) with In Vivo Anti-acute Myeloid Leukemia Activity.","date":"2025","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40702697","citation_count":0,"is_preprint":false},{"pmid":"40424643","id":"PMC_40424643","title":"A meta-analysis to re-evaluate the sensitivity and specificity of FMDV NSP ELISA tests.","date":"2025","source":"Biologicals : journal of the International Association of Biological Standardization","url":"https://pubmed.ncbi.nlm.nih.gov/40424643","citation_count":0,"is_preprint":false},{"pmid":"41155494","id":"PMC_41155494","title":"Are pNF-H, IL-6, BDNF, and NSP Reliable Biomarkers of Cognitive Function in Prostate Cancer Patients?","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41155494","citation_count":0,"is_preprint":false},{"pmid":"4043440","id":"PMC_4043440","title":"Isolation of the homogeneous constituents from non-diffusible sugar-peptide (NSP) fraction originating from bovine plasma. IV. The influence on cell growth of REF and R-XC cells in vitro.","date":"1985","source":"Folia histochemica et cytobiologica","url":"https://pubmed.ncbi.nlm.nih.gov/4043440","citation_count":0,"is_preprint":false},{"pmid":"15953403","id":"PMC_15953403","title":"Haplotypes Eco47 III-Nsp I sites frequencies on the IDUA gene in Mexican native population.","date":"2005","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15953403","citation_count":0,"is_preprint":false},{"pmid":"33503450","id":"PMC_33503450","title":"Oral administration of NSP-116, a free radical scavenger, suppresses the symptoms of retinal vein occlusion in the murine model.","date":"2021","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/33503450","citation_count":0,"is_preprint":false},{"pmid":"40285984","id":"PMC_40285984","title":"Pan-serotype reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay targeting 2B-NSP coding region for colorimetric detection of foot-and-mouth disease virus in clinical samples.","date":"2025","source":"Virus genes","url":"https://pubmed.ncbi.nlm.nih.gov/40285984","citation_count":0,"is_preprint":false},{"pmid":"39721145","id":"PMC_39721145","title":"Lycorine esters exert anti-HCoV-OC43 effect through reversibly acylating cysteine residue in the nsp 12 NiRAN domain.","date":"2024","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39721145","citation_count":0,"is_preprint":false},{"pmid":"3537272","id":"PMC_3537272","title":"Effect of neurotropin (NSP) on the in vivo and in vitro antibody responses in mice.","date":"1986","source":"Journal of pharmacobio-dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/3537272","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48677,"output_tokens":4288,"usd":0.105176},"stage2":{"model":"claude-opus-4-6","input_tokens":7756,"output_tokens":2859,"usd":0.165382},"total_usd":0.270558,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"RTN1 protein isoforms (NSP-A and NSP-C) are anchored to membranes of the endoplasmic reticulum via their common hydrophobic carboxy-terminal domain; deletion mutant analysis revealed that this C-terminal hydrophobic portion is critical for membrane binding. NSP-A co-localizes with SERCA2b, a Ca2+-ATPase of the ER.\",\n      \"method\": \"In vitro translation, immunoprecipitation, Western blot, immunocytochemistry, deletion mutant analysis, subcellular fractionation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — deletion mutagenesis + fractionation + co-localization, foundational study replicated by subsequent work\",\n      \"pmids\": [\"7844160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"NSP-A and NSP-B form supramolecular aggregates (>500 kDa) associated with the membranous fraction of cells, solubilizable by Triton X-100; NSP-B exists in phosphorylated (45 kDa) and non-phosphorylated forms.\",\n      \"method\": \"Gel filtration, immunoprecipitation, immunoblotting, 2D-PAGE, transfection of COS-1 cells\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods in single study\",\n      \"pmids\": [\"7720728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"NSP-C (RTN1-C) localizes to the endoplasmic reticulum and is retained in the membranous fraction solubilizable by Triton X-100; under native immunoprecipitation conditions, NSP-C does not need to associate with NSP-A to form high molecular weight RTN complexes.\",\n      \"method\": \"Immunofluorescence of transfected COS-1 cells, cell fractionation, immunoprecipitation under native conditions, immunoblotting\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (fractionation, IP, IF) in single study\",\n      \"pmids\": [\"8900485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The human NSP/RTN1 gene uses multiple promoters rather than alternative splicing of internal exons to generate distinct mRNA isoforms encoding RTN1 protein isoforms with unique N-terminal regions but a common C-terminal domain.\",\n      \"method\": \"Genomic clone analysis, comparison of genomic and cDNA sequences, lambda phage and YAC library screening\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genomic structural analysis with sequencing evidence\",\n      \"pmids\": [\"8833145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"RTN1 (s-rex/NSP) mRNAs are compartmentalized within neurons: in certain adult brain neurons, most of the shorter s-rexs mRNA and a substantial amount of s-rexb mRNA localize to the axonal pole of the cell body, targeting the encoded proteins to specific neuronal regions.\",\n      \"method\": \"Subtractive hybridization, in situ hybridization, immunolocalization\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — localization tied to functional compartmentalization in neurons\",\n      \"pmids\": [\"8793864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ER localization of RTN1-A requires its two long hydrophobic segments in the C-terminal domain; each segment alone is sufficient for ER targeting, but loss of both results in cytosolic localization. The length of the hydrophobic segment also determines ER retention vs. Golgi localization.\",\n      \"method\": \"EGFP fusion constructs, deletion mutagenesis, fluorescence microscopy in transfected cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with defined functional readout (ER vs. Golgi vs. cytosol localization)\",\n      \"pmids\": [\"17303085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The C-terminal region of RTN1-C (residues 186-208) contains a consensus sequence homologous to H4 histone and binds and condenses nucleic acids. This region also interacts with HDAC8, and its binding can be regulated by acetylation-deacetylation, suggesting RTN1-C function may be regulated by this mechanism.\",\n      \"method\": \"Electrophoretic mobility shift, fluorescence spectroscopy, kinetic assays with acetylated peptide, sequence homology analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro biochemical assays in single study\",\n      \"pmids\": [\"19140693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The RTN1-C C-terminal peptide (residues 186-208) binds copper and nickel ions via an ATCUN-binding motif, and the resulting metal-peptide complex has nuclease activity and inhibits histone deacetylase (HDAC) activity at micromolar concentrations.\",\n      \"method\": \"UV-vis spectroscopy, CD, NMR, kinetic HDAC assays, DNA cleavage assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal in vitro methods, single lab\",\n      \"pmids\": [\"20000484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The RTN1-C C-terminal region contains a metal ion binding motif (HxE/D) that binds copper and nickel; metal binding may contribute to the formation of RTN multiprotein complexes.\",\n      \"method\": \"UV-vis, CD, multidimensional NMR, biological HDAC assays\",\n      \"journal\": \"Metallomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple spectroscopic methods, single lab\",\n      \"pmids\": [\"22522967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RTN1-C physically interacts with MANF (mesencephalic astrocyte-derived neurotrophic factor) in the ER; RTN1-C knockdown reduces MANF localization to the ER, indicating RTN1-C regulates MANF ER retention.\",\n      \"method\": \"Yeast two-hybrid screen of human fetal brain cDNA library, GST pull-down, co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays (Y2H, GST pull-down, Co-IP) plus localization with functional consequence\",\n      \"pmids\": [\"25543119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RTN1A interacts with PERK (an ER stress kinase) through both its N-terminal and C-terminal domains; mutation of these domains prevents RTN1A-mediated induction of ER stress. RTN1 overexpression induces ER stress and apoptosis, while knockdown attenuates ER stress and renal fibrosis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutagenesis, in vivo mouse knockdown (UUO and diabetic models), tunicamycin/hyperglycemia-induced ER stress assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — co-IP with domain mutagenesis + in vivo validation, replicated in multiple disease models\",\n      \"pmids\": [\"26227493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RTN1-C mediates ischemia/reperfusion-induced apoptosis via ER stress and mitochondria-associated pathways; mechanistically, RTN1-C interacts with Bcl-xL and increases Bcl-xL localization to the ER, thereby reducing Bcl-xL anti-apoptotic activity.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, rat MCAO model, OGD/R model, overexpression and siRNA knockdown, flow cytometry, Western blot\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP demonstrating RTN1-C/Bcl-xL interaction, fractionation showing ER relocalization, in vivo confirmation\",\n      \"pmids\": [\"28981095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RTN1 and RTN3 differentially regulate BACE1: RTN3 deficiency causes elevation of BACE1 protein levels, while RTN1 deficiency shows no direct effect on BACE1 due to compensation by upregulated RTN3. RTN1 and RTN3 expression is tightly cross-regulated in mouse brain.\",\n      \"method\": \"RTN1-null and RTN3-null mouse generation, BACE1 activity assays, immunohistochemistry, Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout models with defined molecular and cellular readouts, epistasis analysis\",\n      \"pmids\": [\"28733667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RTN1-C knockdown in SN4741 cells inhibits surface expression of metabotropic glutamate receptor 5 (mGluR5) and attenuates intracellular Ca2+ release induced by MPP+; protective effects of RTN1-C knockdown are partially reversed by mGluR5 activation, indicating RTN1-C regulates mGluR5-mediated Ca2+ homeostasis.\",\n      \"method\": \"siRNA knockdown, Western blot for surface mGluR5, Ca2+ imaging, pharmacological receptor activation\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway placement via pharmacological epistasis and Ca2+ imaging\",\n      \"pmids\": [\"30521940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RTN1-C knockdown in cortical neurons reduces traumatic neuronal injury by attenuating intracellular Ca2+ overload; specifically, RTN1-C knockdown inhibits mGluR1-mediated ER Ca2+ release and suppresses STIM1 expression, thereby reducing store-operated Ca2+ entry (SOCE).\",\n      \"method\": \"siRNA knockdown, Ca2+ imaging, thapsigargin-induced SOCE assay, Western blot for STIM1, cytotoxicity and apoptosis assays\",\n      \"journal\": \"Neurochemistry international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays linking RTN1-C to STIM1/SOCE pathway\",\n      \"pmids\": [\"30352262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RTN1-C expression is upregulated in high glucose/OGD/R-treated neurons and exacerbates ER stress; RTN1-C knockdown reverses high glucose-aggravated cell death and relieves ER stress markers (GRP78, cleaved caspase-12, CHOP, cleaved caspase-3).\",\n      \"method\": \"shRNA knockdown, OGD/R model, Western blot, CCK-8 assay, flow cytometry, 4-PBA ER stress inhibitor\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with multiple molecular readouts, chemical epistasis with ER stress inhibitor\",\n      \"pmids\": [\"31002913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NSP-C (RTN1-C) interacts with CLOCK in mammalian cells and acts as a positive regulator of CLOCK/BMAL1-mediated E-box transcription; NSP-C knockdown suppresses E-box-mediated transcription, and this is rescued by siRNA-resistant NSP-C.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, siRNA knockdown, rescue experiment, E-box reporter assay\",\n      \"journal\": \"Cytotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Y2H + Co-IP + functional transcription assay + rescue in single study\",\n      \"pmids\": [\"30600463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RTN1-C modulates autophagy during cerebral ischemia/reperfusion injury: RTN1-C knockdown suppresses overactivated autophagy (decreased Beclin-1 and other autophagy markers) both in vivo and in vitro, reducing brain infarct volume and neurological deficits; rapamycin (autophagy activator) treatment aggravates injury, and RTN1-C knockdown partially rescues this.\",\n      \"method\": \"Lentiviral shRNA in vivo and in vitro, rat MCAO model, OGD/R model, Western blot for autophagy markers, rapamycin pharmacological epistasis, infarct volume measurement\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo + in vitro KD with pharmacological epistasis\",\n      \"pmids\": [\"33372676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TUG1 lncRNA down-regulates RTN1 expression by inhibiting binding of transcription factor PU.1 to the RTN1 promoter; PU.1 directly transactivates RTN1, and its inhibition by TUG1 reduces ER stress and apoptosis in diabetic nephropathy.\",\n      \"method\": \"Dual-luciferase activity assay, RNA pull-down, RIP, ChIP, adenoviral overexpression in vivo, siRNA knockdown\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP + luciferase + RIP + in vivo validation provide mechanistic placement of PU.1 as RTN1 transcriptional regulator\",\n      \"pmids\": [\"34062006\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RTN1 encodes a family of ER-resident membrane proteins (RTN1-A, -B, -C) anchored via two long hydrophobic C-terminal segments; the RTN1-C isoform interacts with PERK (through N- and C-terminal domains), Bcl-xL (promoting its ER localization and reducing its anti-apoptotic activity), MANF (regulating MANF ER retention), and CLOCK (enhancing circadian transcription), and it modulates intracellular Ca2+ homeostasis through mGluR1/mGluR5 and STIM1-dependent SOCE, collectively driving ER stress, autophagy, and apoptosis in neurons and renal cells under pathological conditions; RTN1 expression is transcriptionally controlled by PU.1, which is in turn suppressed by lncRNA TUG1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RTN1 encodes a family of ER-resident membrane proteins (isoforms RTN1-A, -B, -C) that function as modulators of ER stress, calcium homeostasis, autophagy, and apoptosis, particularly in neurons and renal cells. All isoforms are anchored to ER membranes via two long C-terminal hydrophobic segments, each independently sufficient for ER targeting, and can form high-molecular-weight complexes [PMID:7844160, PMID:17303085, PMID:7720728]. RTN1-C interacts with PERK to induce ER stress signaling [PMID:26227493], sequesters Bcl-xL to the ER to diminish its anti-apoptotic function [PMID:28981095], regulates intracellular Ca²⁺ through mGluR1/mGluR5 surface expression and STIM1-dependent store-operated Ca²⁺ entry [PMID:30521940, PMID:30352262], and positively regulates CLOCK/BMAL1-mediated circadian transcription [PMID:30600463]. RTN1 transcription is directly activated by PU.1, which is suppressed by the lncRNA TUG1, linking RTN1 expression to ER stress and apoptosis in diabetic nephropathy [PMID:34062006].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing that RTN1 isoforms are ER-anchored membrane proteins resolved the fundamental question of where these neuronally enriched proteins reside and act, revealing their C-terminal hydrophobic domain as the membrane-targeting determinant.\",\n      \"evidence\": \"Deletion mutagenesis, subcellular fractionation, and immunocytochemistry in transfected cells showing co-localization with ER marker SERCA2b\",\n      \"pmids\": [\"7844160\", \"7720728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise membrane topology (hairpin vs. transmembrane) was not resolved\", \"No functional consequence of ER localization was demonstrated\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrating that RTN1-C independently forms high-molecular-weight ER complexes without requiring RTN1-A, and that distinct promoters generate isoforms with unique N-termini, established isoform-specific organizational principles.\",\n      \"evidence\": \"Native immunoprecipitation, cell fractionation, immunofluorescence in COS-1 cells; genomic clone and cDNA sequence comparison\",\n      \"pmids\": [\"8900485\", \"8833145\", \"8793864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional differences between isoform-specific complexes were unknown\", \"Identity of other complex subunits was not determined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defining that each of the two C-terminal hydrophobic segments is independently sufficient for ER targeting, and that segment length controls ER versus Golgi retention, resolved the structural basis of RTN1 ER residency.\",\n      \"evidence\": \"EGFP-fusion deletion constructs with fluorescence microscopy readout in transfected cells\",\n      \"pmids\": [\"17303085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No reconstitution of membrane curvature or tubulation activity\", \"In vivo relevance of hydrophobic segment length variants was not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying a histone H4-homologous region in RTN1-C that binds and condenses nucleic acids and interacts with HDAC8, regulated by acetylation, revealed an unexpected potential for chromatin-related regulation by an ER protein.\",\n      \"evidence\": \"EMSA, fluorescence spectroscopy, kinetic assays with acetylated peptide, sequence homology analysis\",\n      \"pmids\": [\"19140693\", \"20000484\", \"22522967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of nucleic acid binding by an ER-resident protein is unclear\", \"Metal-binding nuclease activity demonstrated only in vitro with isolated peptides\", \"Not independently confirmed by another laboratory\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that RTN1-C physically interacts with MANF and is required for MANF ER retention provided the first evidence that RTN1 functions as an ER retention factor for a secreted neurotrophic factor.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown in cells\",\n      \"pmids\": [\"25543119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of retention (direct anchoring vs. retrieval) was not distinguished\", \"In vivo consequences of MANF mislocalization upon RTN1 loss were not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating that RTN1A directly interacts with the ER stress kinase PERK through both N- and C-terminal domains, and that RTN1 overexpression induces ER stress while knockdown attenuates renal fibrosis in vivo, established RTN1 as an upstream activator of the UPR.\",\n      \"evidence\": \"Co-immunoprecipitation with domain deletion mutagenesis, in vivo mouse UUO and diabetic models with RTN1 knockdown\",\n      \"pmids\": [\"26227493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RTN1 activates PERK by direct conformational change or by altering ER membrane structure was not resolved\", \"Specificity for PERK versus other UPR sensors (IRE1, ATF6) was not fully addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying RTN1-C as a binding partner of Bcl-xL that redirects Bcl-xL to the ER and reduces its anti-apoptotic activity linked RTN1-C to mitochondria-associated apoptotic pathways during ischemia/reperfusion injury.\",\n      \"evidence\": \"Co-immunoprecipitation, subcellular fractionation, rat MCAO model, OGD/R model, siRNA knockdown\",\n      \"pmids\": [\"28981095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Bcl-xL sequestration is the primary pro-apoptotic mechanism or secondary to ER stress was not resolved\", \"Binding interface on Bcl-xL was not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing that RTN1-C knockdown inhibits mGluR1/mGluR5 surface expression and STIM1-dependent store-operated Ca²⁺ entry revealed RTN1-C as a regulator of ER-to-plasma-membrane Ca²⁺ signaling in neurons.\",\n      \"evidence\": \"siRNA knockdown, Ca²⁺ imaging, thapsigargin-induced SOCE assay, pharmacological mGluR activation in neuronal cell lines and cortical neurons\",\n      \"pmids\": [\"30521940\", \"30352262\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between RTN1-C and mGluR or STIM1 was not demonstrated\", \"Whether Ca²⁺ dysregulation is upstream or downstream of ER stress was not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that RTN1-C interacts with CLOCK and enhances CLOCK/BMAL1-mediated E-box transcription expanded RTN1-C function beyond ER stress to circadian gene regulation.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown with rescue, E-box luciferase reporter assay in mammalian cells\",\n      \"pmids\": [\"30600463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The subcellular compartment where RTN1-C–CLOCK interaction occurs was not defined\", \"Physiological circadian phenotype upon RTN1 loss was not tested in vivo\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Establishing that RTN1-C drives overactivated autophagy during cerebral ischemia/reperfusion, and that its transcription is controlled by PU.1 (itself inhibited by lncRNA TUG1), placed RTN1 at the convergence of transcriptional regulation, ER stress, and autophagy.\",\n      \"evidence\": \"Lentiviral shRNA in rat MCAO and OGD/R models with rapamycin epistasis; ChIP, luciferase, RIP, and RNA pull-down for PU.1/TUG1 axis in diabetic nephropathy models\",\n      \"pmids\": [\"33372676\", \"34062006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether autophagy modulation is a direct RTN1-C function or secondary to ER stress/Ca²⁺ dysregulation is unknown\", \"Integration of PU.1-mediated transcription with neuronal injury contexts was not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of RTN1 membrane topology and curvature induction, whether RTN1 isoforms have non-redundant functions in vivo, and how RTN1-C coordinates its diverse interactions (PERK, Bcl-xL, CLOCK, MANF, mGluRs) in a single cell.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of RTN1 in membranes\", \"No conditional knockout addressing isoform-specific functions\", \"Hierarchy among RTN1-C's pro-apoptotic, Ca²⁺-regulatory, circadian, and autophagic roles is not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 11, 13, 14, 16]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 5, 9, 10, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [10, 11, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11, 15, 17]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PERK\", \"BCL2L1\", \"MANF\", \"CLOCK\", \"STIM1\", \"HDAC8\", \"PU.1\"],\n    \"other_free_text\": []\n  }\n}\n```"}